Structure and Functional Characterization of Human Histidine Triad Nucleotide-Binding Protein 1 Mutations Associated with Inherited Axonal Neuropathy with Neuromyotonia.

Autor: Shah RM; Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA., Maize KM; Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA., West HT; Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA., Strom AM; Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA., Finzel BC; Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA., Wagner CR; Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA; Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: wagne003@umn.edu.
Jazyk: angličtina
Zdroj: Journal of molecular biology [J Mol Biol] 2018 Aug 17; Vol. 430 (17), pp. 2709-2721. Date of Electronic Publication: 2018 May 19.
DOI: 10.1016/j.jmb.2018.05.028
Abstrakt: Inherited peripheral neuropathies are a group of neurodegenerative disorders that clinically affect 1 in 2500 individuals. Recently, genetic mutations in human histidine nucleotide-binding protein 1 (hHint1) have been strongly and most frequently associated with patients suffering from axonal neuropathy with neuromyotonia. However, the correlation between the impact of these mutations on the hHint1 structure, enzymatic activity and in vivo function has remained ambiguous. Here, we provide detailed biochemical characterization of a set of these hHint1 mutations. Our findings indicate that half of the mutations (R37P, G93D and W123*) resulted in a destabilization of the dimeric state and a significant decrease in catalytic activity and HINT1 inhibitor binding affinity. The H112N mutant was found to be dimeric, but devoid of catalytic activity, due to the loss of the catalytically essential histidine; nevertheless, it exhibited high affinity to AMP and a HINT1 inhibitor. In contrast to the active-site mutants, the catalytic activity and dimeric structure of the surface mutants, C84R and G89V, were found to be similar to the wild-type enzyme. Taken together, our results suggest that the pathophysiology of inherited axonal neuropathy with neuromyotonia can be induced by conversion of HINT1 from a homodimer to monomer, by modification of select surface residues or by a significant reduction of the enzyme's catalytic efficiency.
(Copyright © 2018. Published by Elsevier Ltd.)
Databáze: MEDLINE
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